Update on FIP: Reasons for Optimism

Feline Enteric Coronavirus (Fecv)

Feline enteric coronavirus is an enveloped single strand RNA virus that is associated with asymptomatic, persistent and enteric infections. It is found worldwide and is ubiquitous in domestic and wild felines. There are 2 serotypes: 80% to 95% are serotype 1 (cat-like), 5% to 20% are serotype 2 (dog-like). Serotype 2 has a higher incidence in Asia than in North America and Europe. Clinically inapparent infection of kittens can start after weaning at 9 to 10 weeks of age. Virus shedding in feces, can persist for many weeks months or longer. Fecal-Oral transmission is facilitated by shared litter boxes. The virus displays tropism for the mature, apical epithelium of the lower intestine. Immunity develops slowly. Immunity is lost after shedding ceases, and recurrent infections are common.

Kittens can make IGM antibody and mount cell mediated immune responses from birth. IGG and IGA antibodies are absorbed from colostrum during the first few hours of life. Passive, systemic immunity results, from IGG and IGA from colostrum. Passive local immunity is derived from IGG and IGA antibiotics in the milk. Passive, systemic and local immunity protects kittens until their immune system matures. IGG and IGA production does not start until passive antibody is gone at 6 to 8 weeks of age. Kittens’ immune systems do not reach adult levels until 12 to 16 weeks of age.

Kittens born to FECV exposed Queens, will have maternal immunity until 9 weeks of age. Primary infection will evoke both a systemic and a local antibody response. IGA goes from blood, transmitted across the intestinal epithelium into the mucus. There is no evidence of cell mediated immunity or any changes in lymphocyte populations. The IGA antibody response slowly leads to the cessation of virus shedding. Antibody titers wane as virus, shedding, ceases and cats, become susceptible to reinfection. Immunity to FECV infection is transient and recurrent infections are common.

Feline Infectious Peritonitis Virus (FIP)

FIP arises from FECV, infection by mutation. FIPVs occur in regional lymphoid tissues of the lower intestine and 10% of FEC V, infected cats. Mutations result from positive selection pressures favoring replication in macrophages. FIPVs acquire tropism for peritoneal macrophages and lose tropism for intestinal epithelium. Tropism change results from mutations in Spike s and accessory 3C genes. FIP V mutation is unique to each cat. If FIPVS are strictly cell associated and local and systemic spread is in monoocytes and macrophages. FIPV is confined to infected macrophages which are not spread from cat to cat. There are rare cases of cat to cat spread (epidemic form) Serotype II FIPV.

FEC, be infections occur in virtually all cats and kittens. FECV to FIPV biotype conversion, occurs in eleven percent of cats. Only 1 in 10 to 1 in 30 cats with mutant viruses develop FIP. Worldwide feline mortality among all cats due to FIP is thought to be point 3 percent to 1.3 percent. FIP favors, multi-cat environments: Catteries, foster homes, rescue groups, shelters and cats living in dense, urban areas. if there is additional stress in these environments, the odds of FIP occurring increases. 95% of cases occurring cats, less than 7 years of age. 70% in cats less than 1.5 years of age. 50 percent in cats, less than 7 months of age. Pedigree Cats have 3 times greater incidence of FIP than random bred cats. Males are slightly more susceptible.

Pathophysiology

Macrophages are infected by immune complex, virus through their FC receptors. FIP is typical of other macrocphage infections, such as tuberculosis, leprosy , and deep mycosis. FIP is mediated by cytokine responses of infected macrophages. Th 1cell mediated cytokine responses are protective. Protective immunity is innate at onset and then becomes adaptive. Failure to establish protective immunity leads to th2 inflammatory response and disease. Affected cats have delayed apoptosis of infected macrophages, allowing for increased virus production. The incubation period from first replication in macrophages, to clinical disease is days to months. The actual disease course, varies from days to months and rarely a year or more. Once typical disease signs appear, historically, fewer than 5 percent of affected cats have survived to 1 year.

There are 2 major disease forms effusive and non-effusive. Wet and dry FIP Resemble the lepromatous and tuberculoid forms of human leprosy respectively. The 2 forms of FIPV are dependent on the relative balance of cellular and humoral immune responses. Wet FIPV is characterized by a predominance of immediate hypersensitivity reactions, vasculitis, And high levels of virus replication and macrophages. Dry FIP is characterized by a predominance of delayed hypersensitivity reactions and low levels of virus replication in macrophages. The disease form in a cat, may change from wet FIPV to dry FIP, or dry to wet during the course of the illness.

Diagnosis

In most cases a diagnosis of FIPV can be made by obtaining a complete history and performing a thorough exam of the patient and using the following diagnostic tools to build a diagnostic wall” brick by brick.

• High index of Suspicion and playing the odds.
• Signal meant age, breed origin Typically shelter / sanctuary or other dense multi-cat situations.
• Sudden loss of activity, lethargy, anorexia weight loss.
• Failure to thrive. Smaller than normal, poor hair, coat thin.
• Recent stressful event: Vaccination, surgery, new home, relinquished to a shelter or foster home, other illnesses.
• Physical exam and presence of signs associated with FIPV: Jaundice, ascites, pleural fluid uveitis or retinitis neurologic sign, palpable abdominal masses.

Basic non-definitive tests

Complete, blood count may show anemia of chronic disease Leukocytosis or lymphopenia. Serum proteins Often have a total protein high with albumin and globulin, an Albumin:globulin, ratio of less than 0.6 With the lowest albumin:globulin ratios tending to be in cats with wet FIPV, rather than dry. Bilirubin is elevated, in 21% to 63% of FIPV cases, often without marked elevation in hepatic enzyme activity. Feline coronavirus antibiotics Titer cannot determine if antibody titers are against FECV or FIPV. Abdominal and or thoracic effusions, maybe, yellow tinged, mucinous with partial clots., cloudy, containing non-degenerate neutrophils, monocytes, macrophages, or large foamy mcrophages and lymphocytes. Fluid protein may be 2 to 10 plus grams per deciliter. A Rivalta Test, should not replace a complete fluid analysis. but the test is inexpensive and easy to perform. Images for evidence of effusion and or organ and/or central lymph node, involvement include radiographs, abdominal ultrasound, MRI scans, with contrast and complete ophthalmic exam.

Definitive diagnosis occurs, when FECV / FIPV RNA is identified in effusion or diseased tissue. Histopathologic or microscopic appearance of lesions is not pathognomonic unless combined with the rest of the clinical picture. Immunohistochemistry positive for Coronavirus antigen in macrophages within effusions of diseased tissues. Polymerase chain reaction (rt-PCR) must have enough FIPV RNA in the effusion sample. FCOV 7b RNA PCR Is most sensitive. FIPV s mutation RNA is less sensitive. Positive 7B RNA test is diagnostic, even if the S mutation test is negative. PCR on blood is not highly sensitive. If you confirm the presence of FIPV virus antigen or RNA within peritoneal type macrocephages within typical effusions or lesions, you have made a definitive diagnosis. However, this is compounded by all the false negative test results that are made by laboratories using poor techniques, or that have been given non-representative samples.

Treatment

Current non-FDA-approved, antiviral drug status. FIPV is now considered a curable disease. Anecdotally, thousands of cats worldwide have been treated and possibly cured with antiviral compounds. Reversal of severe signs for both wet and dry forms of FIPV Can be seen within days of starting antiviral treatment. Recurrent known drug with the most significant Success for curing, FIPV is GS – 441524, Nucleoside analog produced by Gilead Sciences, which is under patent and not available for veterinary use. AniVive LifeSciences Incorporated is working to gain FDA approval of GC 376 as a treatment for FIPV.

Several companies in China, have developed what they suggest are similar or the same compound drug products and are b marketing these products worldwide as dietary supplements to treat FIPV. The compounds have not received, generally recommended as safe status (GRAS). Under us, FDA restrictions the use of non GRAS compounds in veterinary health care is illegal. Those treating cats with FIPV are acquiring a version of GS4 441524 Through online or non-Veterinary resources such as members of the public referred through Facebook groups. No assurances are available as to bioactivity ,safety, toxicity, and identity of the compounds being used in these non-FDA approved substances. The course of treatment recommended can be expensive. Prices vary among companies and whether cost is related to the quality of the product remains unknown. Suppliers of GS441524, should be chosen with care. No centralized data is being maintained a reviewed under scientific supervision. Veterinarians cannot prescribed, or dispensed these non-approved compounds. they can though choose to provide supportive and monitoring care for cats undergoing treatment. Establishing a good veterinarian client patient. Relationship is in the best interest of the patient.

Complex Risk

Stressful conditions have a tremendous impact on virus shedding. There are multiple mutations that cause disease from reservoirs of FECV in crowded conditions. Every virus shed is an experiment in potential mutation and exposure of cats to that mutation. Reducing the environmental viral load is a critical component in prevention. Stress appears to trigger disease in some cats. However, tools for accurately analyzing stress triggers, may be somewhat lacking. Nutrition, lack of passive immunity for orphaned kittens, nd gastrointestinal dysbiosis are all worthy of investigating as possible stressors. Distinguishing, the role of stress from the role of comorbid conditions is not yet possible.

Strong Immune response and Virus elimination may occur for only a period of time. FECV does not induce durable immunity. Immunity wanes and cats become susceptible again. Passive, maternal antibodies are highly protective and may be useful in creating more durable immunity. Innate cellular immunity. is required in turn, requires growing, FECV serotype 1, in cell culture for vaccine development.

Strong Immune response and Virus elimination may occur for only a period of time. FECV does not induce durable immunity. Immunity wanes and cats become susceptible again. Passive, maternal antibodies are highly protective and may be useful in creating more durable immunity. Innate cellular immunity. is required in turn, requires growing, FECV serotype 1, in cell culture for vaccine development.

According to a recent study, certain Bentonite based cat litters can decrease viral shedding and environmental contamination. However, the clinical significance has not yet been demonstrated. Early, weaning of kittens is not desirable as passive immunity from colostrum And lactation can effectively protect kittens from coronavirus infection. A Corona virus Free environment is Not Practical as reinfection is nearly impossible to prevent.

In well-run shelters today FIPV is not a common problem. A well-functioning shelter should see less than 1% FIPV cases. Shelter should balance intake with healthy outcomes by reduced crowding, thus decreasing virus shedding and exposure to infectious disease. One study showed FECV shedding increased millions fold in some cats after a week in the shelter. Developing fostering programs. No bottle raised kittens or Queens with kittens, should not come into the shelter, but go straight into foster homes. This lessens the odds of exposure to all infectious diseases, including FIPV. Using double compartment and closures with 8.5 square feet of floor, space leads to a 50% decrease in the exposure to upper respiratory infections. Placing portal between compartments, decreases the incidence of respiratory disease by 90%. Group housing is not ideal for cats. If grouped place no more than 3 to 5 cats in each group. Keep the group, stable note in, and out movement of cats. Don’t mix long and short stay cats.

Our mission to end FIP is not finished. Research must continue in such areas as improving diagnostic methods, developing additional antiviral drugs and especially strategies to prevent FIPV infection in cats.

Summary

1. Feline Enteric Corona virus (FECV) and Feline Infectious Peritonitis virus (FIP) are very different viruses that cause much different forms of infection.
2. FIP diagnosis is not as difficult as clinicians make it. Because until recently, it has been a fatal diagnosis, clinicians have tried to find other causes of signs that are more promising.
3. FIPV is now considered a curable disease. Anecdotally, thousands of cats worldwide have been treated and possibly cured with antiviral compounds.
4. Veterinarians cannot prescribed, or dispense these non-approved compounds. they can though choose to provide supportive and monitoring care for cats undergoing treatment.
5. Stressful conditions have a tremendous impact on virus shedding

References

• Tekelioglu BK, Berriatua E, Turan N, et al. (2015) A retrospective clinical and epidemiological study on feline coronavirus (FCoV) in cats in Istanbul, Turkey. Prev Vet Med.;119(1-2):41-7
• Fish EJ, Diniz PPV, Juan YC, et al. (2018) Cross-sectional quantitative RT-PCR study of feline coronavirus viremia and replication in peripheral blood of healthy shelter cats in Southern California. J Feline Med Surg:295-301.
• Pedersen, NC, Colleran EJ, Dale, S. et al. WINN FIP SYMPOSIUM PURRsuing FIP and WINNing November 16 & 17, 2019 University Of California At Davis, California
• This Disease Information Fact Sheet accompanies the 2013 AAFP Feline Vaccination Advisory Panel Report published in the Journal of Feline Medicine and Surgery (2013), Volume 15, pp 785–808.
• Pedersen NC, Perron M, Bannasch M, et al. (2019) Efficacy and safety of the nucleoside analog GS-441524 for treatment of cats with naturally occurring feline infectious peritonitis. J Feline Med Surg. (4):271-281.
• Dickinson, PJ, Bannasch m, Thomasy, SM. (2020) Antiviral treatment using the adenosine nucleoside analogue GS-441524 in cats with clinically diagnosed neurological feline infectious peritonitis J Vet Intern Med.;34:1587–1593.
• Personal communication: Niels Pedersen 2021, FIP Warriors 5.0